Background and Objective: University students are among vulnerable groups to tendency towards substance use. Accordingly, this study aimed to investigate the role of personal, familial, and social risk and protective factors in the prediction of tendency to this behavior among students. Materials and Methods: This descriptive correlational study was carried out on 431 students of Shahid Beheshti University of Medical Sciences who were selected by convenience sampling. Data were collected by Risk and Protective Factors Inventory (RPFI) and Youth Risk Taking Scale (YRTS) and then, were analyzed by Pearson correlation method and stepwise multivariate regression.Results: Data analysis using Pearson Correlation Coefficient showed significant relationships between personal (e.g. attitude towards substance use and tendency to drug use; r=0.6, P<0.01), familial (e.g. parent attitude towards substance and tendency towards smoking cigarettes; r=0.2, P<0.05), and social (e.g. perceived accessibility and tendency towards alcohol; r=0.4, P<0.01) factors with tendency to substance use. Moreover, the results of stepwise multivariate regression analysis indicated that personal factors (i.e. attitude towards substance use, sensation seeking, and impulsivity), social factors (i.e. friends’ substance use and perceived accessibility), and familial factors (i.e. family monitoring and parents’ attitude towards substance use) were the best predictors of tendency towards substance use in students, respectively.Conclusion: In conclusion, current results indicated that a series of individual, familial, and social factors affect tendency towards substance use among students. Accordingly, identifying vulnerable students using suitable screening tests and providing them with primary prevention programs is of the utmost importance.